Enhanced bimatoprost ophthalmic solution

ABSTRACT

A composition comprising from 0.005% to 0.02% bimatoprost by weight and from 100 ppm to 250 ppm benzalkonium chloride, wherein said composition is an aqueous liquid which is formulated for ophthalmic administration is disclosed herein. 
     A method which is useful in treating glaucoma or ocular hypertension related thereto is also disclosed herein.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/561,592, filed Dec. 4, 2014, which is a continuation of U.S. patentapplication Ser. No. 14/100,914, filed Dec. 9, 2013, now U.S. Pat. No.8,933,120, issued Jan. 13, 2015, which is a continuation of U.S. patentapplication Ser. No. 13/827,774, filed Mar. 14, 2013, now U.S. Pat. No.8,772,338, issued Jul. 8, 2014, which is a continuation of U.S. patentapplication Ser. No. 13/715,332, filed Dec. 14, 2012, now U.S. Pat. No.8,586,630, issued Nov. 19, 2013, which is a continuation of U.S. patentapplication Ser. No. 13/370,574, filed Feb. 10, 2012, now U.S. Pat. No.8,278,353, issued Oct. 2, 2012, which is a continuation of U.S. patentapplication Ser. No. 13/370,529, filed Feb. 10, 2012, now U.S. Pat. No.8,299,118, issued Oct. 30, 2012, which is a continuation of U.S. patentapplication Ser. No. 12/965,514, filed Dec. 10, 2010, now U.S. Pat. No.8,309,605, issued Nov. 13, 2012, which is a continuation of U.S. patentapplication Ser. No. 12/351,383, filed Jan. 9, 2009, now U.S. Pat. No.8,338,479, issued Dec. 25, 2012, which is a continuation of U.S. patentapplication Ser. No. 11/083,261, filed Mar. 16, 2005, now U.S. Pat. No.7,851,504, issued Dec. 14, 2010, all of which are hereby incorporatedherein by reference.

FIELD OF THE INVENTION

This invention relates to pharmaceutical compositions comprisingbimatoprost.

BACKGROUND OF THE INVENTION Description of Related Art

Bimatoprost, shown below, is a prostamide marketed commercially for thetreatment of glaucoma and ocular hypertension.

Benzalkonium chloride (BAK) is a preservative used in many commercialophthalmic products to prevent microbial contamination in multi-useproducts. The commercial eye drops (Bimatoprost, Allergan, Inc., Irvine,Calif.) contain 0.03% bimatoprost and 0.005% BAK. Although no otherprostamides are currently marketed for the treatment of glaucoma,several prostaglandin analogs are commercially available which use BAKas a preservative. These include latanoprost (Xalatan), travoprost(Travatan), and unoprostone isopropyl (Rescula), which requiresignificantly more BAK, from 150-200 ppm, to meet antimicrobialeffectiveness tests in the United States and Europe.

U.S. Pat. No. 6,596,765 B2 discloses a composition comprising 0.005% or0.0005% latanoprost and 0.2 mg/mL BAK.

U.S. Pat. No. 6,646,001 B2 discloses compositions comprising 0.03%bimatoprost and 0.01% BAK or “0.01%+5% excess” BAK.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 is a plot showing the aqueous humor concentration of the parentacid of bimatoprost after topical administration of severalformulations.

FIG. 2 is a plot showing the membrane permeability of bimatoprost inseveral different formulations.

DETAILED DESCRIPTION OF THE INVENTION

A composition comprising from 0.005% to 0.02% bimatoprost by weight andfrom 100 ppm to 250 ppm benzalkonium chloride, wherein said compositionis an aqueous liquid which is formulated for ophthalmic administrationis disclosed herein.

A method which is useful in treating glaucoma or ocular hypertensionrelated thereto is also disclosed herein.

An aqueous liquid which is formulated for ophthalmic administration isformulated such that it can be administered topically to the eye. Thecomfort should be maximized as much as possible, although sometimesformulation considerations (e.g. drug stability) may necessitate lessthan optimal comfort.

In certain compositions the concentration of bimatoprost is from 0.01%to 0.02%. In other compositions the concentration of bimatoprost is from0.015% to 0.02%.

In certain compositions the concentration of BAK is from 150 ppm to 200ppm. In other compositions the concentration of BAK is from 150 ppm to200 ppm. In other compositions the concentration of BAK is from 150 ppmto 250 ppm.

In ophthalmic compositions, a chelating agent may be used to enhancepreservative effectiveness. Suitable chelating agents are those known inthe art, and, while not intending to be limiting, edetate salts (EDTA)are useful chelating agents.

In certain compositions, concentration of EDTA is at least 0.001%. Inother compositions, the concentration of EDTA is at least 0.01%. Inother compositions the concentration of EDTA is 0.15% or less. In othercompositions the concentration of EDTA is 0.1% or less. In othercompositions the concentration of EDTA is 0.05% or less.

Certain compositions comprise from 150 to 250 ppm BAK and an effectiveamount of EDTA.

As is known in the art, buffers are commonly used to adjust the pH to adesirable range for ophthalmic use. Generally, a pH of around 6-8 isdesired, and in certain compositions a pH of 7.4 is desired. Manybuffers including salts of inorganic acids such as phosphate, borate,and sulfate are known.

Another commonly used excipient in ophthalmic compositions is aviscosity-enhancing, or a thickening agent. Thickening agents are usedfor a variety of reasons, ranging from improving the form of theformulation for convenient administration to improving the contact withthe eye to improve bioavailability. The viscosity-enhancing agent maycomprise a polymer containing hydrophilic groups such asmonosaccharides, polysaccharides, ethylene oxide groups, hydroxylgroups, carboxylic acids or other charged functional groups. While notintending to limit the scope of the invention, some examples of usefulviscosity-enhancing agents are sodium carboxymethylcellulose,hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, andpolyethylene glycol.

In ophthalmic solutions, tonicity agents often are used to adjust thecomposition of the formulation to the desired isotonic range. Tonicityagents are well known in the art and some examples include glycerin,mannitol, sorbitol, sodium chloride, and other electrolytes.

One composition has a pH of 7.4 and consists essentially of 0.015%bimatoprost, 200 ppm benzalkonium chloride, from 0 to 0.03% EDTA, aphosphate buffer, NaCl, and water.

Another composition has a pH of 7.4 and comprises 0.02% bimatoprost, 200ppm benzalkonium chloride, from 0 to 0.03% EDTA, a phosphate buffer,NaCl, and water.

Another composition has a pH of 7.4 and consists of 0.01% bimatoprost,200 ppm benzalkonium chloride, from 0 to 0.03% EDTA, a phosphate buffer,NaCl, and water.

The best mode of making and using the present invention are described inthe following examples. These examples are given only to providedirection and guidance in how to make and use the invention, and are notintended to limit the scope of the invention in any way.

One embodiment comprises 0.01% Bimatoprost, 0.02% Benzalkonium Chloride,0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% Citric Acid,Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is 7.3.

Another embodiment comprises 0.015% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

Another embodiment comprises 0.015% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, 0.03%, EDTA, and water,wherein the pH is 7.3.

Another embodiment comprises 0.02% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

Another embodiment consists essentially of 0.01% Bimatoprost, 0.02%Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate,0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, and water,wherein the pH is 7.3.

Another embodiment consists essentially of 0.015% Bimatoprost, 0.02%Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate,0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, and water,wherein the pH is 7.3.

Another embodiment consists essentially of 0.015% Bimatoprost, 0.02%Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate,0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, 0.03%, EDTA, andwater, wherein the pH is 7.3.

Another embodiment consists essentially of 0.02% Bimatoprost, 0.02%Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate,0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, and water,wherein the pH is 7.3.

Another embodiment consists of 0.01% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

Another embodiment consists of 0.015% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

Another embodiment consists of 0.015% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, 0.03%, EDTA, and water,wherein the pH is 7.3.

Another embodiment consists of 0.02% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

EXAMPLE 1

Formulations containing 0.268% sodium phosphate dibasic heptahydrate,0.014% citric acid, 0.83% sodium chloride, with the pH adjusted to 7.3in qs water, and the amounts of bimatoprost, BAK, and EDTA listed inTable 1 below were prepared by conventional methods well known in theart.

TABLE 1 Formulation 1. 0.03% Bimatoprost (50 ppm BAK) Control 2. 0.03%Bimatoprost - 200 ppm BAK 3. 0.03% Bimatoprost - 0.015% TPGS (nopreservative) 4. 0.03% Bimatoprost - 0.2% TPGS (no preservative) 5.0.03% Bimatoprost - 0.4% TPGS (no preservative) 6. 0.03% Bimatoprost -1.0% TPGS (no preservative)

EXAMPLE 2

Studies were carried out to determine the effect of benzalkoniumchloride (BAK) and d-alpha tocopheryl polyethylene glycol 1000 succinate(TPGS) on ocular absorption of bimatoprost in vivo. For the in vivostudy, eighteen female rabbits were given a single 28 μL eyedropbilaterally and aqueous humor samples were collected (n=3 animals with 6eyes per formulation) at 60 min postdose. Two rabbits (4 eyes) remaineduntreated to serve as pre-dose bioanalytical controls. Bimatoprost andits parent carboxylic acid extracted from aqueous humor and in vitrosamples were analyzed by a liquid chromatography tandem massspectrometry (LC-MS/MS) method with a quantitation range of 0.25-60ng/mL.

Due to extensive metabolism of bimatoprost in rabbit eyes, its parentacid was used as a surrogate for determining ocular absorption ofbimatoprost. Concentration of the acid in rabbit aqueous humor followingsingle dose of 6 different bimatoprost formulations are summarized inFIG. 1 and Table 2 below.

TABLE 2 Aqueous Formulation Humor^(a) (ng/mL) 1. 0.03% Bimatoprost (50ppm BAK) Control 51.0 ± 9.4 2. 0.03% Bimatoprost - 200 ppm BAK 87.2 ±19.0* 3. 0.03% Bimatoprost - 0.015% TPGS (no 26.1 ± 3.3* preservative)4. 0.03% Bimatoprost - 0.2% TPGS (no preservative) 22.9 ± 3.2* 5. 0.03%Bimatoprost - 0.4% TPGS (no preservative) 19.3 ± 5.6* 6. 0.03%Bimatoprost - 1.0% TPGS (no preservative) 15.4 ± 3.3* ^(a)Mean ± SD. Performulation, N = 3 rabbits (6 eyes). *Statistically different (p < 0.05)compared to 0.03% Bimatoprost

Test formulations containing 0.015%, 0.2%, 0.4% and 1.0% TPGS resultedin a lower aqueous humor carboxylic acid concentration compared toBimatoprost by 52%, 59%, 62% and 72%, respectively. In contrast, 0.03%Bimatoprost containing 200 ppm BAK resulted in 57% higher aqueous humorAGN 191522 concentration compared to Bimatoprost (50 ppm BAK).

While not intending to limit the scope of the invention in any way, orbe bound by theory, compared to the Bimatoprost control, formulationscontaining TPGS resulted in decrease bimatoprost permeability. Incontrast, formulations with higher BAK resulted in higher permeability.

EXAMPLE 3

Formulations containing 0.268% sodium phosphate dibasic heptahydrate,0.014% citric acid, 0.83% sodium chloride, with the pH adjusted to 7.3in qs water, and the amounts of bimatoprost, BAK, and EDTA listed inTable 3 below were prepared by conventional methods well known in theart.

TABLE 3 Formulation A. 0.03% Bimatoprost (50 ppm BAK) - Control B.0.015% Bimatoprost (50 ppm BAK) C. 0.015% Bimatoprost (50 ppm BAK) 0.03%EDTA D. 0.015% Bimatoprost (200 ppm BAK) E. 0.015% Bimatoprost (200 ppmBAK) 0.03% EDTA F. 0.015% Bimatoprost (50 ppm BAK) 0.015% EDTA G. 0.015%Bimatoprost (200 ppm BAK) 0.015% EDTA H. 0.015% Bimatoprost (125 ppmBAK) I. 0.015% Bimatoprost (125 ppm BAK) 0.03% EDTA J. 0.015%Bimatoprost (125 ppm BAK) 0.015% EDTA K. 0.015% Bimatoprost (150 ppmBAK) L. 0.015% Bimatoprost (150 ppm BAK) 0.1% EDTA M. 0.015% BimatoprostN. 0.03% Bimatoprost

EXAMPLE 4

The effect of benzalkonium chloride (BAK) and ethylenediaminetetraaceticacid (EDTA) on bimatoprost permeability across primary culture of rabbitcorneal epithelial cell layers (RCECL). Corneal epithelial cells wereharvested from New Zealand White rabbits and cultured on Transwell™filters until confluency (Day 5). For the transport experiment, cellswere first equilibrated in transport buffer for 1 hour at 37° C. Dosingsolution containing 0.015% or 0.03% bimatoprost with varyingconcentrations of BAK and EDTA was then applied to the apicalcompartment of the Transwell™ (2 cultures; n=3-4 per culture) and thecells were incubated at 37° C. At 30, 60, 90 and 120 minutes postdose,200 μL samples were taken from the basolateral chamber for apical tobasolateral (AB) transport. The samples were analyzed by a liquidchromatography tandem mass spectrometry (LC-MS/MS) method withquantitation range of 1-600 ng/mL.

The results are presented in FIG. 2.

EXAMPLE 5

A drop of formulation J is administered once daily topically to the eyeof a person suffering from glaucoma. After a few hours, intraocularpressure drops more and less hyperemia is observed than would beobserved for formulation A. Lowered intraocular pressure persists for aslong as the treatment continues.

What is claimed is:
 1. An ophthalmic composition comprising about0.01%-0.015% w/v bimatoprost and about 0.02% w/v benzalkonium chloride.2. The ophthalmic composition of claim 1, wherein the compositioncomprises about 0.01% w/v bimatoprost.
 3. The ophthalmic composition ofclaim 1, wherein the composition comprises 0.01% w/v bimatoprost.
 4. Theophthalmic composition of claim 1, wherein the composition comprisesabout 0.015% w/v bimatoprost.
 5. The ophthalmic composition of claim 1,wherein the composition comprises 0.015% w/v bimatoprost.
 6. Theophthalmic composition of claim 1, wherein the composition comprises0.02% w/v benzalkonium chloride.
 7. The ophthalmic composition of claim1, wherein the composition further comprises dibasic sodium phosphate.8. The composition of claim 1, wherein the first composition furthercomprises citric acid monohydrate.
 9. The composition of claim 1,wherein the composition further comprises sodium chloride.
 10. Thecomposition of claim 1, wherein the first composition further compriseshydrochloric acid and sodium hydroxide to adjust the pH.
 11. Thecomposition of claim 1, wherein the composition further comprises water.12. The composition of claim 1, wherein the first composition has a pHof about 7.3.
 13. The composition of claim 1, wherein the compositioncomprises 0.01% w/v bimatoprost and 0.02% w/v benzalkonium chloride, andwhen applied to the eyes of a human patient suffering from elevatedintraocular pressure, lowers intraocular pressure and results in lesshyperemia than a second composition comprising 0.03% w/v bimatoprost and0.005% w/v benzalkonium chloride.
 14. The composition of claim 13,wherein the composition applied once daily lowers intraocular pressureas effectively as the second composition applied once daily.
 15. Thecomposition of claim 13, wherein the composition is applied to the eyesof a human patient suffering from elevated intraocular pressure at leastonce a day.
 16. The composition of claim 13, wherein the compositionapplied once daily lowers intraocular pressure more effectively than thesecond composition applied once daily.
 17. The composition method ofclaim 13, wherein the composition applied once daily is effective fortreating glaucoma.
 18. The composition of claim 1, wherein thecomposition comprises 0.01% w/v bimatoprost and 0.02% w/v benzalkoniumchloride, and when applied once daily to the eyes of a human patientsuffering from elevated intraocular pressure, lowers intraocularpressure and results in less hyperemia than a second compositioncomprising 0.03% w/v bimatoprost and 0.005% w/v benzalkonium chloride.19. The composition of claim 18, wherein the composition applied oncedaily lowers intraocular pressure as effectively as the secondcomposition applied once daily.
 20. The composition method of claim 18,wherein the composition applied once daily is effective for treatingglaucoma.